【０００１】[0001]
【発明の属する技術分野】本発明は、水難溶性薬物封入
ポリマーミセルを含有する製剤の製造方法、および該製
造方法で得ることのできる凍結乾燥製剤に関する。TECHNICAL FIELD The present invention relates to a method for producing a preparation containing a poorly water-soluble drug-encapsulated polymer micelle, and a freeze-dried preparation obtainable by the production method.
【０００２】[0002]
【従来の技術】親水性セグメントおよび疎水性セグメン
トを有するブロックコポリマーを使用して水難溶性薬物
を封入した高分子ミセルの製造方法の典型的なものとし
ては、例えば、特許第２７７７５３０号公報に記載の以
下のａ）、ｃ）の方法、ならびに特開２００１−２２６
２９４号公報に記載の下記ｄ）の方法が知れている。ａ） 撹拌による薬物の封入法水難溶性薬物を、必要により水混和性の有機溶媒に溶解
して、ブロックコポリマー分散水溶液と撹拌混合する。
なお、撹拌混合時に加熱することにより薬物の高分子ミ
セル内への封入を促進できる場合もある。ｂ） 溶媒揮散法水難溶性薬物の水非混和性の有機溶媒溶液とブロックコ
ポリマー分散水溶液とを混合し、撹拌しながら有機溶媒
を揮散させる。ｃ） 透析法水混和性の有機溶媒に水難溶性薬物およびブロックコポ
リマーを溶解した後、得られる溶液を透析膜を用い緩衝
液および／または水に対して透析する。ｄ） その他水非混和性の有機溶媒に水難溶性薬物およびブロックコ
ポリマーを溶解し、得られる溶液を水と混合し、撹拌し
て水中油（Ｏ／Ｗ）型エマルジョンを形成し、次いで有
機溶媒を揮散させる。2. Description of the Related Art A typical method for producing a polymeric micelle in which a poorly water-soluble drug is encapsulated using a block copolymer having a hydrophilic segment and a hydrophobic segment is described in, for example, Japanese Patent No. 2777530. The following methods a) and c), and JP-A-2001-226
The following method d) described in Japanese Patent No. 294 is known. a) Encapsulation Method of Drug by Stirring A poorly water-soluble drug is dissolved in a water-miscible organic solvent, if necessary, and stirred and mixed with the block copolymer-dispersed aqueous solution.
In some cases, heating during stirring and mixing can promote the encapsulation of the drug in the polymer micelles. b) Solvent volatilization method A water-immiscible organic solvent solution of a poorly water-soluble drug is mixed with a block copolymer-dispersed aqueous solution, and the organic solvent is volatilized while stirring. c) Dialysis method After the poorly water-soluble drug and the block copolymer are dissolved in a water-miscible organic solvent, the resulting solution is dialyzed against a buffer and / or water using a dialysis membrane. d) A poorly water-soluble drug and a block copolymer are dissolved in another water-immiscible organic solvent, the resulting solution is mixed with water and stirred to form an oil-in-water (O / W) type emulsion, and then the organic solvent is added. Volatilize.
【０００３】さらに、該薬物とブロックコポリマーを有
機溶媒に溶解し、両者を均一に混合した後溶媒を留去
し、次いで固体の均一混合物を６０℃または４０℃で水
に溶解して薬物封入ポリマーミセル溶液を調製する、所
謂、固体分散法または溶媒蒸発法とも称されている方法
も提案されている（例えば、Park et. al., Biomateria
ls and Drug Delivery toward New Mellenium, ２００
０，３２１−３３２；Lavasanifar et. al., Journal o
f Controlled Release ７７（２００１）１５５−１６
０参照）。これらの方法では、除菌濾過に一般的に用い
られる孔径が０.２２μｍフィルターを通過する薬物封
入ポリマーミセルを含有する液が得られている。例え
ば、後者の刊行物によると、薬物（アンホテリシンＢ）
封入ポリマーミセルが７３％の収率で得られ、ミセル溶
液をフィルター（０.２２μｍ）で濾過し、凍結乾燥し
て得られる凍結乾燥物を水で再溶解（reconstitute）
し、再度、濾過（０.２２μｍ）したことも記載されて
いる。このような再溶解または再構成液は、注射剤とし
て使用しうる可能性も示唆されている。なお、上記の従
来法では有機溶媒として一般的にジクロロメタンが用い
られている。しかし、こうして調製される医薬製剤がヒ
トに直接適用されることを考慮すると、生体に対して毒
性の懸念されるジクロロメタン等の使用を避けることが
好ましい。Further, the drug and the block copolymer are dissolved in an organic solvent, both are uniformly mixed, the solvent is distilled off, and then the solid homogeneous mixture is dissolved in water at 60 ° C. or 40 ° C. A method for preparing a micelle solution, which is also called a so-called solid dispersion method or solvent evaporation method, has been proposed (for example, Park et. Al., Biomateria.
ls and Drug Delivery toward New Mellenium, 200
0,321-332; Lavasanifar et. Al., Journal o.
f Controlled Release 77 (2001) 155-16
0). According to these methods, a liquid containing a drug-encapsulating polymer micelle which has a pore size of 0.22 μm and is generally used for sterilization filtration is obtained. For example, according to the latter publication, the drug (amphotericin B)
Encapsulated polymer micelles were obtained with a yield of 73%, the micellar solution was filtered through a filter (0.22 μm), and the freeze-dried product obtained by freeze-drying was redissolved in water (reconstitute).
However, it is also described that the solution was filtered (0.22 μm) again. It has been suggested that such a reconstituted or reconstituted solution may be used as an injection. In the above conventional method, dichloromethane is generally used as the organic solvent. However, considering that the pharmaceutical preparation thus prepared is directly applied to humans, it is preferable to avoid the use of dichloromethane or the like, which may be toxic to the living body.
【０００４】[0004]
【発明が解決しようとする課題】上記の Lavasanifar e
t. al., の方法によれば、ポリマーミセル内への薬物の
かなり高い封入効率が達成できるようである。[Problems to be Solved by the Invention] Lavasanifar e
According to the method of T. al., a considerably higher encapsulation efficiency of the drug in the polymer micelles can be achieved.
【０００５】しかし、一般的には極めて高価な薬物をポ
リマーミセル内に封入するに際し、所望のポリマーミセ
ルサイズを有し、しかも薬物の封入効率の高い薬物封入
ポリマーミセルを提供することは、依然として必要であ
ろう。一般的に、これまでの方法は、生体に毒性がある
と言われているジクロロメタンを使用している。したが
って、本発明の目的は、制御された粒径の薬物封入ポリ
マーミセルの改善された製造方法またはかかるポリマー
ミセルを含有する製剤の製造方法を提供すること、なら
びに生体に対して毒性の懸念がないかまたは毒性のない
溶媒を用いることのできる製造方法を提供することにあ
る。However, in encapsulating a drug, which is generally very expensive, in a polymer micelle, it is still necessary to provide a drug-encapsulating polymer micelle having a desired polymer micelle size and having a high drug encapsulation efficiency. Will. Generally, previous methods use dichloromethane which is said to be toxic to living organisms. Accordingly, it is an object of the present invention to provide an improved process for the preparation of drug-loaded polymeric micelles of controlled particle size, or of a formulation containing such polymeric micelles, as well as the risk of toxicity to living organisms. Another object of the present invention is to provide a production method capable of using a solvent that is free of toxicity.
【０００６】[0006]
【課題を解決するための手段】本発明者らは、上記の目
的を達成すべく、薬物封入ポリマーミセルの製造方法に
ついて多面的に検討してきた。その結果、上述の固体分
散法または溶媒蒸発法において、薬物と一定のブロック
コポリマーの均一固定混合物を水中に均一分散させると
きの温度が３０℃を境界とし、それ以下では、所望の粒
径、殊に、注射剤としてそのまま使用できるような粒径
の薬物封入ポリマーミセルの収率を確実、かつ、有意に
高めうることを見出した。すなわち、上記の方法には、
効率を高める上で、操作温度として約３０℃付近に臨界
点が存在することが確認された。[Means for Solving the Problems] In order to achieve the above-mentioned objects, the present inventors have conducted multifaceted studies on a method for producing drug-encapsulating polymer micelles. As a result, in the above-mentioned solid dispersion method or solvent evaporation method, the temperature at which a uniform fixed mixture of a drug and a certain block copolymer is uniformly dispersed in water has a boundary of 30 ° C., and below that, a desired particle size, especially In addition, it was found that the yield of the drug-encapsulating polymer micelle having a particle size that can be used as an injection as it is can be increased reliably and significantly. That is, in the above method,
It was confirmed that a critical point exists at an operating temperature of about 30 ° C. in order to improve efficiency.
【０００７】したがって、本発明によれば、親水性セグ
メントと疎水性セグメントを含んでなるブロックコポリ
マーおよび水難溶性薬物を揮散性の有機溶媒に分散溶解
して溶液を形成した後、該有機溶媒を除去し、こうして
得られる残存物を水と一緒にし、次いで該残存物が水に
均一分散するのに十分な時間、３０℃以下の温度で撹拌
することを特徴とする制御された粒径の薬物封入ポリマ
ーミセルを含有する製剤の製造方法が提供される。Therefore, according to the present invention, a block copolymer containing a hydrophilic segment and a hydrophobic segment and a poorly water-soluble drug are dispersed and dissolved in a volatile organic solvent to form a solution, and then the organic solvent is removed. And encapsulating the retentate thus obtained with water and then stirring at a temperature below 30 ° C. for a time sufficient to disperse the retentate in water uniformly, a drug encapsulation of controlled particle size A method of making a formulation containing polymer micelles is provided.
【０００８】該製造方法によれば、通常、注射用製剤を
調製する際の除菌濾過に用いられる孔径０.２２μｍの
フィルターを通過しうる薬物封入ポリマーミセルが７３
％を超える薬物封入率で得られる。したがって、本発明
に従えば、本発明方法によって製造され、そして０.２
２μｍのフィルターを通過させた薬物封入ポリマーミセ
ルの水性溶液は、例えばそのまま注射剤として使用でき
る。他方、この注射剤に利用されなかった薬物、存在す
るとしたら、０.２２μｍのフィルターを通過しなかっ
たもの等は、わずかな量であるため、殆ど回収すること
なく無視することができるであろう。According to the above-mentioned production method, 73 drug-encapsulating polymer micelles that can pass through a filter having a pore size of 0.22 μm, which is usually used for sterilization filtration when preparing an injectable preparation, are prepared.
Obtained with a drug encapsulation rate of more than%. Therefore, according to the invention, it is produced by the method of the invention and
The aqueous solution of the drug-encapsulating polymer micelle that has been passed through a 2 μm filter can be used, for example, as it is as an injection. On the other hand, drugs that were not used for this injection, such as those that did not pass through the 0.22 μm filter, were so small that they could be ignored without being recovered. .
【０００９】該薬物封入ポリマーミセル含有液を０.２
２μｍのフィルターを通過させる前に該水性溶液に、場
合により緩衝剤、その他の助剤を添加する態様も、本発
明の一つの態様である。かような助剤として、糖類や特
定分子量のポリエチレングリコール（薬局法上、マクロ
ゴールと称されてもいる）を用いると、０.２２μｍの
フィルターを通過する濾液を凍結乾燥すると、相当する
凍結乾燥製剤が得られ、このような製剤は水性溶液に再
溶解または再構成した場合でも、複数のポリマーミセル
相互間での凝集が抑制されるとの、さらなる効果も得ら
れる。薬剤の種類によっては、上記のごとき凝集が避け
られない場合がよくあることを考えると、上記の助剤を
添加する構成の採用は、極めて重要である。The drug-encapsulating polymer micelle-containing liquid was added to 0.2
An embodiment in which a buffering agent and other auxiliary agents are optionally added to the aqueous solution before passing through a 2 μm filter is also an embodiment of the present invention. When saccharides or polyethylene glycol having a specific molecular weight (also called macrogol in the Pharmacopoeia method) is used as such an auxiliary agent, freeze-drying the filtrate that passes through a 0.22 μm filter causes the corresponding freeze-drying. A formulation is obtained, and even when such a formulation is redissolved or reconstituted in an aqueous solution, an additional effect is obtained in that aggregation between a plurality of polymer micelles is suppressed. Considering that agglomeration as described above is often unavoidable depending on the type of the drug, it is extremely important to adopt the configuration in which the above-mentioned auxiliary agent is added.
【００１０】本発明によれば、上記の製造方法により得
ることができ、上述したように、水性溶液に再構成した
とき、ポリマーミセル間で凝集が殆ど生じない凍結乾燥
製剤も提供される。According to the present invention, there is also provided a lyophilized preparation which can be obtained by the above-mentioned production method and, as described above, causes little aggregation between polymer micelles when reconstituted in an aqueous solution.
【００１１】[0011]
【発明の具体的な態様】本発明で用いることのできる親
水性セグメントと疎水性セグメントを含んでなるブロッ
クコポリマーは、水性溶液または媒体中において、水難
溶性薬物の共存下で疎水性コア領域と親水性シエル領域
をもつポリマーミセルを形成でき、そして本発明の目的
に沿うものであれば、いかなるブロックコポリマーをも
包含する。限定されるものでないが、このようなブロッ
クコポリマーの親水性セグメントとしては、ポリ（エチ
レングリコール）［または、ポリ（エチレンオキシド）
とも称される］、ポリ（リンゴ酸）、ポリ（サッカライ
ド）、ポリ（アクリル酸）、ポリ（ビニルアルコール）
等が挙げられる。他方、疎水性セグメントとしては、ポ
リ（β−アルキルアスパルテート）、ポリ（β−アルキ
ルアスパルテート−コ−アスパラギン酸）、ポリ（β−
アラルキルアスパルテート）、ポリ（β−アラルキルア
スパルテート−コ−アスパラギン酸）、ポリ（β−アル
キルアスパルタミド）、ポリ（β−アルキルアスパルタ
ミド−コ−アスパラギン酸）、ポリ（β−アラルキルア
スパルタミド）、ポリ（β−アラルキルアスパルタミド
−コ−アスパラギン酸）、ポリ（γ−アルキルグルタメ
ート）、ポリ（γ−アルキルグルタメート−コ−グルタ
ミン酸）、ポリ（γ−アラルキルグルタメート）、ポリ
（γ−アラルキルグルタメート−コ−グルタミン酸）、
ポリ（γ−アルキルグルタミド）、ポリ（γ−アルキル
グルタミド−コ−グルタミン酸）、ポリ（γ−アラルキ
ルグルタミド）、ポリ（γ−アラルキルグルタミド−コ
−グルタミン酸）、ポリ（ラクチド）、ポリ（ラクチド
−コ−グリコリド）、ポリ（ε−カプロラクトン）、ポ
リ（δ−バレロラクトン）およびポリ（γ−ブチロラク
トン）が挙げられる、なお、上記のセグメント中におけ
る、アルキルおよびアラルキルは、それぞれ以下の意味
を有する。アルキルとしては、Ｃ1−Ｃ22の直鎖もしく
は分岐のアルキルであり、メチル、エチル、ｎ−プロピ
ル、ｉ−プロピル、ｎ−ブチル、ｔ−ブチル、ｎ−ヘキ
シル等の低級アルキル、さらに炭素数の多い中級アルキ
ル、また、テトラデシル、ヘキサデシル、オクトデシ
ル、ドコサニル等が挙げられる。これらの基は、場合に
より、１以上のハロゲン（例えば、フッ素、塩基、臭
素）で置換されていてもよく、また、中〜高級アルキル
にあっては、１個の水酸基で置換されていてもよい。ア
ラルキルとしては、フェニル−Ｃ1−Ｃ4アルキル、例え
ばベンジルを挙げることができ、場合によって、ベンゼ
ン環上で１〜３個のハロゲンまたは低級アルキルによっ
て置換されていてもよい。BEST MODE FOR CARRYING OUT THE INVENTION A block copolymer comprising a hydrophilic segment and a hydrophobic segment, which can be used in the present invention, has a hydrophilic core region and a hydrophilic core region in an aqueous solution or medium in the presence of a poorly water-soluble drug. Included are any block copolymers that are capable of forming polymeric micelles having a polymeric shell region and that are consistent with the purposes of the present invention. The hydrophilic segment of such a block copolymer includes, but is not limited to, poly (ethylene glycol) [or poly (ethylene oxide)].
Also called], poly (malic acid), poly (saccharide), poly (acrylic acid), poly (vinyl alcohol)
Etc. On the other hand, as the hydrophobic segment, poly (β-alkyl aspartate), poly (β-alkyl aspartate-co-aspartic acid), poly (β-
Aralkyl aspartate), poly (β-aralkylaspartate-co-aspartic acid), poly (β-alkylaspartamide), poly (β-alkylaspartamide-co-aspartic acid), poly (β-aralkyla) Spartamide), poly (β-aralkylaspartamide-co-aspartic acid), poly (γ-alkylglutamate), poly (γ-alkylglutamate-co-glutamic acid), poly (γ-aralkylglutamate), poly (γ -Aralkyl glutamate-co-glutamic acid),
Poly (γ-alkyl glutamide), poly (γ-alkyl glutamide-co-glutamic acid), poly (γ-aralkyl glutamide), poly (γ-aralkyl glutamide-co-glutamic acid), poly (lactide), poly (Lactide-co-glycolide), poly (ε-caprolactone), poly (δ-valerolactone) and poly (γ-butyrolactone) are included, wherein alkyl and aralkyl in the above segments have the following meanings respectively. Have. The alkyl is a C1 -C22 linear or branched alkyl, which is a lower alkyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-hexyl and the like, and further has a carbon number. There are many common intermediate alkyls, and also tetradecyl, hexadecyl, octodecyl, docosanyl and the like. These groups may optionally be substituted with one or more halogens (eg fluorine, base, bromine) and, in medium to higher alkyl, may be substituted with one hydroxyl group. Good. Aralkyl may include phenyl-C1 -C4 alkyl, such as benzyl, optionally substituted on the benzene ring by 1 to 3 halogens or lower alkyl.
【００１２】このようなポリマーセグメントは、それ自
体公知の、例えば、ポリ（β−ベンジルアスパルテー
ト）またはポリ（γ−ベンジルグルタメート）のベンジ
ル基を相当するアルコールまたはアミンによるエステル
またはアミド交換することによって得ることができる。
疎水性ポリマーセグメントが共重合体として表示されて
いるのは、対応するアルキル−もしくはアラルキル−エ
ステルもしくはアミドを部分エステル化又は、部分加水
分解することにより得られる。部分エステル化の程度
は、一般的に、２０〜８０％であることができる。ま
た、アスパラギン酸、グルタミン酸、ラクチドは、いず
れかの光学活性型のものであるか、それらの混合物であ
ることができる。Such polymer segments are obtained by transesterification or amide exchange of the benzyl group of poly (β-benzyl aspartate) or poly (γ-benzyl glutamate) known per se with the corresponding alcohol or amine. Obtainable.
The indication of the hydrophobic polymer segment as a copolymer is obtained by partial esterification or partial hydrolysis of the corresponding alkyl- or aralkyl-ester or amide. The degree of partial esterification can generally be 20-80%. Further, aspartic acid, glutamic acid, and lactide can be any optically active type or a mixture thereof.
【００１３】以上のような親水性セグメントと疎水性セ
グメントは、水難溶性薬物の共存下の水性溶液（または
水性媒体）中でポリマーミセルを形成しうるものであれ
ば、それぞれのセグメントの大きさに制限がないが、一
般的には、上記のような親水性セグメントは、その繰り
返し単位が３０〜１０００にあり、他方、疎水性セグメ
ントは、その繰り返し単位が１０〜１００にある。な
お、本明細書に記載するところの水性溶液または水性媒
体とは、水そのもの、または緩衝剤溶液または媒体を意
味する。As long as the hydrophilic segment and the hydrophobic segment as described above can form a polymer micelle in an aqueous solution (or an aqueous medium) in the coexistence of a poorly water-soluble drug, the size of each segment is different. Although not limited, in general, hydrophilic segments as described above have repeating units in the range of 30 to 1000, while hydrophobic segments have repeating units in the range of 10 to 100. In addition, the aqueous solution or the aqueous medium described in the present specification means water itself or a buffer solution or medium.
【００１４】特に、製造容易であり、本発明で都合よく
使用できるブロックコポリマーとしては、下記式（Ｉ）
および（ＩＩ）で示すことのできるものを挙げることが
できる。Particularly, a block copolymer which is easy to produce and can be conveniently used in the present invention is represented by the following formula (I).
And (II) can be mentioned.
【００１５】[0015]
【化２】[Chemical 2]
【００１６】上記各式中Ｒ1およびＲ3は、それぞれ独立
して、水素原子または保護されていてもよい官能基が置
換したもしくは未置換低級アルキル基を表し、Ｒ2は水
素原子、飽和もしくは不飽和のＣ1〜Ｃ29脂肪族カルボ
ニル基またはアリールカルボニル基を表し、Ｒ4は水酸
基、飽和もしくは不飽和のＣ1〜Ｃ30脂肪族オキシ基ま
たはアリール−低級アルキルオキシ基を表し、Ｒ5はベ
ンジル又はアルキルベンジル、アリルを表し、Ｌ1およ
びＬ2は、それぞれ独立して連結基を表し、ｎは１０〜
２５００の整数であり、ｘおよびｙは、同一もしくは異
なり、それらの合計が１０〜３００となる整数であり、
そしてｘ対ｙが７：３〜１：３の範囲内にあり、かつｘ
およびｙは、それぞれランダムに存在する。保護されて
いてもよい官能基としては、ヒドロキシル基、アセター
ル、ケタール、アルデヒド、糖残基等が挙げられる。Ｒ
1およびＲ3が保護されていてもよい官能基が置換した低
級アルキル基を表す場合の親水性セグメントは、例え
ば、ＷＯ９６／３３２３３、ＷＯ９６／３２４３４、Ｗ
Ｏ９７／０６２０２に記載の方法に従うことができる。In the above formulas, R1 and R3 each independently represent a hydrogen atom or a lower alkyl group substituted or unsubstituted by an optionally protected functional group, and R2 is a hydrogen atom, saturated or R5 represents an unsaturated C1 -C29 aliphatic carbonyl group or arylcarbonyl group, R4 represents a hydroxyl group, a saturated or unsaturated C1 -C30 aliphatic oxy group or an aryl-lower alkyloxy group, R5 Represents benzyl or alkylbenzyl, allyl, L1 and L2 each independently represent a linking group, and n represents 10 to 10.
Is an integer of 2500, x and y are the same or different, and their sum is 10 to 300,
And x to y is in the range of 7: 3 to 1: 3, and x
And y are randomly present. Examples of the functional group which may be protected include a hydroxyl group, an acetal, a ketal, an aldehyde and a sugar residue. R
When 1 and R3 represent a lower alkyl group substituted with an optionally protected functional group, the hydrophilic segment is, for example, WO96 / 33233, WO96 / 32434, W.
The method described in O97 / 06202 can be followed.
【００１７】連結基は、主として、ブロックコポリマー
の製造方法により変化しうるので限定されるものでない
が、具体的なものとしては、Ｌ1が−ＮＨ−、−Ｏ−、
−ＣＯ−、−ＣＨ2−、−Ｏ−Ｚ−Ｓ−Ｚ−および−Ｏ
ＣＯ−Ｚ−ＮＨ−、−Ｏ−Ｚ−ＮＨ（ここで、Ｚは独立
してＣ1〜Ｃ4アルキレン基である。）からなる群より選
ばれ、Ｌ2が−ＯＣＯ−Ｚ−ＣＯ−および−ＮＨＣＯ−
Ｚ−ＣＯ−、−Ｏ−Ｚ−ＮＨ（ここで、ＺはＣ1〜Ｃ4ア
ルキレン基である。）からなる群より選ばれる基を挙げ
ることができる。The linking group is not particularly limited because it can be changed mainly depending on the method for producing the block copolymer, but specific examples thereof include L1 --NH--, --O--,
-CO -, - CH 2 -, - O-Z-S-Z- and -O
CO-Z-NH -, - O-Z-NH (. , Where, Z is C1 -C4 alkylene group independently) selected from the group consisting of, L2 is -OCO-Z-CO- And -NHCO-
Z-CO -, - O- Z-NH ( wherein, Z is C1 -C4 alkylene group.) Can be a group selected from the group consisting of.
【００１８】本発明で使用できる水難溶性薬物には、常
温（２５℃）において、その溶解度が水１ｍｌ当たり
０.５ｍｇ以下である有機化合物または有機化合物の複
合体を意味し、本発明の目的上、何らかの薬理作用を有
するものが包含される。このような薬物の代表的なもの
としては、パクリタキセルまたはその誘導体（例えば、
ドセタキシル）、カンプトテシンまたはその誘導体（例
えば、イリノテカン）、シスプラチン、ダウノルビシ
ン、ドキソルビシン、メトトレキサート、マイトマイシ
ンＣ、ビンクレスチン、アンホテリシンＢ、ナイスタチ
ン、プロスタグランジン類およびマクロライド系抗生物
質が挙げられる。The poorly water-soluble drug that can be used in the present invention means an organic compound or a complex of organic compounds, the solubility of which is 0.5 mg or less per 1 ml of water at room temperature (25 ° C.), and for the purpose of the present invention. , Those having some pharmacological action are included. Typical of such drugs are paclitaxel or its derivatives (eg,
Docetaxyl), camptothecin or a derivative thereof (for example, irinotecan), cisplatin, daunorubicin, doxorubicin, methotrexate, mitomycin C, vincrestin, amphotericin B, nystatin, prostaglandins and macrolide antibiotics.
【００１９】本発明方法では、上記のブロックコポリマ
ーと薬物を揮散性の有機溶媒に分散溶解する。分散溶解
するとは、溶質たるブロックコポリマーと薬物とを完全
に溶解した状態だけでなく、可溶化され、例えば、ポリ
マーミセルとして分散している状態にすることを意味す
る。また、本明細書で溶液という場合、上記のような分
散状態をも包含することがあることに注意されたい。こ
のような目的で使用することのできる溶媒としては、生
体に対して毒性の懸念される溶媒を使用せずに該目的を
達成できるものであれば、いかなる溶媒であってもよい
が、例えば、メチルアルコール、エチルアルコール、イ
ソプロピルアルコール、アセトン、アセトニトリル、酢
酸メチル、酢酸エチル、テトラヒドロフラン、ジエチル
エーテル、シクロヘキサン等およびこれらの混合溶媒の
常温で揮散性（すなわち、気化する傾向）を有するもの
を挙げることができる。上記分散溶解は、薬物の特性で
加熱することが可能であれば、溶媒の沸点まで加熱して
よいが、常温以下、溶媒の凝固点を超える温度で溶質を
均質撹拌することにより実施する。In the method of the present invention, the above block copolymer and drug are dispersed and dissolved in a volatile organic solvent. Dispersion and dissolution means not only a state in which the solute block copolymer and the drug are completely dissolved but also a state in which the block copolymer and the drug are solubilized and are dispersed as, for example, polymer micelles. It should be noted that the term “solution” as used herein may include the dispersed state as described above. As the solvent that can be used for such a purpose, any solvent may be used as long as it can achieve the purpose without using a solvent that may be toxic to the living body. Methyl alcohol, ethyl alcohol, isopropyl alcohol, acetone, acetonitrile, methyl acetate, ethyl acetate, tetrahydrofuran, diethyl ether, cyclohexane and the like, and those having a volatility (that is, a tendency to vaporize) of these mixed solvents at room temperature may be mentioned. it can. The dispersion and dissolution may be performed up to the boiling point of the solvent as long as it can be heated due to the characteristics of the drug, but it is carried out by homogeneously stirring the solute at room temperature or lower and at a temperature higher than the freezing point of the solvent.
【００２０】こうして溶液を形成した後、必要により減
圧下で溶媒を蒸発除去する。本発明では、溶媒は必ずし
も完全に除去する必要はないが、溶媒除去後の残存物が
ペースト状ないし固形状を保つようになればよい。しか
し、その後得られる薬物封入ポリマーミセル含有水性溶
液をそのまま注射剤とする場合には、溶媒は実質的に完
全に除去されることが好ましい。After forming the solution in this way, the solvent is evaporated off under reduced pressure, if necessary. In the present invention, the solvent does not necessarily have to be completely removed, but it is sufficient that the residue after removal of the solvent can maintain a paste or solid state. However, when the resulting drug-encapsulated polymer micelle-containing aqueous solution is directly used as an injection, it is preferable that the solvent be substantially completely removed.
【００２１】次に、ペースト状ないしは固形状の残存物
を水と一緒にし（残存物に水を加えるか、または水に残
存物を加えてもよい）、３０℃以下、好ましくは２５℃
以下、より好ましくは１０℃または５℃以下の温度で撹
拌する。必要により、超音波をかけてもよい。この撹拌
は、ブロックコポリマーと薬物とからなる残存物が、ほ
ぼ完全に均一分散されるのに十分な時間行われる。ポリ
マーの種類および薬物の種類によって均一分散される時
間は変動するので限定されないが、一般的に、５時間以
上、２４時間以内の撹拌時間が好ましいであろう。残存
物と水の量比は、１：１０〜１：３００であることがで
きる。Next, the paste-like or solid residue is combined with water (water may be added to the residue or the residue may be added to water), and the temperature is 30 ° C. or lower, preferably 25 ° C.
Hereafter, stirring is carried out at a temperature of 10 ° C. or 5 ° C. or less. If necessary, ultrasonic waves may be applied. The stirring is carried out for a time sufficient to allow the residue consisting of the block copolymer and the drug to be almost completely uniformly dispersed. The time of uniform dispersion varies depending on the type of polymer and the type of drug, and is not limited, but generally, stirring time of 5 hours or more and 24 hours or less will be preferable. The ratio of the amount of the residue to the amount of water may be 1:10 to 1: 300.
【００２２】こうして、水溶液中には、薬物封入ポリマ
ーミセルが形成され、存在する。本発明方法に従えば、
薬物封入ポリマーミセルは、ダイナミック光散乱光度計
（大塚電子（株）、ＤＬＳ−７０００ＤＨ型）で測定し
たところ、可溶化するときの温度を約３０°に設定する
と平均粒子径が約１４０ｎｍであり、孔径０.２２ｍμ
（２２０ｎｍ）のフィルターを通過する粒子が約７３％
を超える。なお、可溶化するときの温度を約２５℃に設
定すると、０.２２μｍのフィルターを通過するポリマ
ーミセルの割合は一般的に約８０％を超え、約１０℃に
設定すると、０.２２μｍのフィルターを通過するポリ
マーミセルの割合は、一般的に約９０％を超えることに
なる。Thus, drug-encapsulating polymer micelles are formed and present in the aqueous solution. According to the method of the present invention,
The drug-encapsulated polymer micelle was measured with a dynamic light scattering photometer (Otsuka Electronics Co., Ltd., DLS-7000DH type), and when the temperature for solubilization was set to about 30 °, the average particle diameter was about 140 nm, Pore size 0.22 mμ
About 73% of the particles pass through the (220 nm) filter
Over. When the temperature for solubilization is set to about 25 ° C, the proportion of polymer micelles that pass through the 0.22 μm filter generally exceeds about 80%, and when set to about 10 ° C, the 0.22 μm filter is used. The percentage of polymeric micelles that will pass through will generally be greater than about 90%.
【００２３】０.２２μｍのフィルターは、通常、注射
剤（静脈注射用、動脈注射用、筋肉注射用、腹腔内注射
用、等）の調製に際して、使用されることが公知であ
る。上記薬物封入ポリマーミセル水溶液は、０.２２μ
ｍのフィルターを用いて除菌濾過しても、上述のとお
り、極めて高収率で除菌済み薬物封入ポリマーミセル水
溶液が得られることになる。すなわち、本発明によれ
ば、注射剤が効率よく提供できる。このような注射剤
は、本発明の好適な態様の一つとして、薬物封入ポリマ
ーミセルの安定性を向上させうる助剤、各種の糖類およ
び各種のポリエチレングリコール（商品名、マクロゴー
ル）を、除菌濾過前の薬物封入ポリマーミセル水溶液
（または水性溶液）に加える工程をさらに含んでなる方
法により製造できる。限定されるものでないが、使用で
きる糖類としては、マルトース、トレハロース、キシリ
トール、グルコース、スクロース、フルクトース、ラク
トース、マンニトールおよびデキストリン等が挙げら
れ、使用できるポリエチレングリコールとしては、分子
量が約１０００〜約３５０００であって、例えば、マク
ロゴール１０００、１５４０、４０００、６０００、２
００００および３５０００等が挙げられる。これらの助
剤は、上記残存物と水とを一緒にするとき、水に含めて
いても、あるいは残存物からの薬物封入ポリマーミセル
が水中に分散溶解した後に加え、その後、全体を除菌濾
過してもよい。こうして、本発明によれば、注射剤中で
薬物封入ポリマーミセルを安定化しうる助剤を注射剤に
簡易、かつ、安全に加えることができる。It is known that a 0.22 μm filter is usually used in the preparation of injections (intravenous injection, arterial injection, intramuscular injection, intraperitoneal injection, etc.). The above drug-encapsulating polymer micelle aqueous solution has a concentration of 0.22μ
Even if the sterilization filtration is performed using the m filter, as described above, the sterilized drug-encapsulated polymer micelle aqueous solution can be obtained in an extremely high yield. That is, according to the present invention, an injection can be efficiently provided. As one of the preferred embodiments of the present invention, such an injection is prepared by removing an auxiliary agent that can improve the stability of drug-encapsulated polymer micelles, various sugars, and various polyethylene glycols (trade name, Macrogol). It can be produced by a method further comprising a step of adding to the drug-encapsulated polymer micelle aqueous solution (or aqueous solution) before bacterial filtration. The sugars that can be used include, but are not limited to, maltose, trehalose, xylitol, glucose, sucrose, fructose, lactose, mannitol, and dextrin. So, for example, Macrogol 1000, 1540, 4000, 6000, 2
0000 and 35000 and the like. These auxiliaries are added when the above residue and water are combined together, even if they are included in water, or after the drug-encapsulating polymer micelles from the residue are dispersed and dissolved in water, and then the whole is sterilized by filtration. You may. Thus, according to the present invention, an auxiliary agent capable of stabilizing the drug-encapsulating polymer micelle in the injection can be easily and safely added to the injection.
【００２４】このような注射剤は簡易、かつ、安全に製
造できるだけでなく、それらを凍結乾燥した場合には、
乾燥製剤を水または水性溶液を用いて薬物封入ポリマー
ミセル含有溶液に再溶解または再構成するときでも、ミ
セル粒子間での凝集がほとんど起こらない注射液が提供
できる。このような凍結乾燥製剤は、本発明者らが知る
限りでは文献未載であり、新規である。したがって、本
発明によれば、該凍結乾燥製剤も提供される。Not only can such injections be manufactured simply and safely, but when they are lyophilized,
Even when the dry formulation is redissolved or reconstituted in a drug-encapsulating polymer micelle-containing solution using water or an aqueous solution, it is possible to provide an injectable solution in which aggregation between micelle particles hardly occurs. Such a freeze-dried preparation has not been published in the literature and is novel as far as the present inventors know. Therefore, according to the present invention, the freeze-dried preparation is also provided.
【００２５】凍結乾燥製剤が上記のような作用効果を奏
するには、凍結乾燥前の溶液における糖類は、その最終
濃度が０.１〜１５重量％になるように加え、ポリエチ
レングリコールはその最終濃度が０.５〜１０重量％に
なるように加えるのがよい。通常、ブロックコポリマー
と糖類またはポリエチレングリコールとの割合は、それ
ぞれ重量で１：１〜１：１０または１：０.５〜１：１
０である。In order for the freeze-dried preparation to exert the above-mentioned effects, the saccharide in the solution before freeze-drying is added so that the final concentration thereof is 0.1 to 15% by weight, and polyethylene glycol is added at the final concentration. Is preferably added in an amount of 0.5 to 10% by weight. Usually, the ratio of block copolymer to sugar or polyethylene glycol is 1: 1 to 1:10 or 1: 0.5 to 1: 1 by weight, respectively.
It is 0.
【００２６】[0026]
【実施例】以下、水難溶性薬物としてパクリタキセルを
用いた場合の例を挙げ、本発明をさらに具体的に説明す
るが、他の薬剤についても同様な結果が得られることが
理解されている。実施例１〜５ならびに比較例１および２使用したブロックコポリマー：ポリエチレングリコール
（分子量１２０００）５０％加水分解ポリアスパラギン
酸ベンジルエステル（ｎ＝５０）（以下、ＰＥＧ−ＰＢ
ＬＡ１２−５０Ｐ.Ｈ．５０％という）EXAMPLES The present invention will be described in more detail below with reference to an example of using paclitaxel as a poorly water-soluble drug, but it is understood that similar results can be obtained with other drugs. Examples 1 to 5 and Comparative Examples 1 and 2 Block copolymer used: polyethylene glycol (molecular weight 12000) 50% hydrolyzed polyaspartic acid benzyl ester (n = 50) (hereinafter PEG-PB
LA12-50P.H. 50%)
【００２７】[0027]
【化３】[Chemical 3]
【００２８】ｎ：ポリ（エチレングリコール）の分子量
が約１２０００になるような数ｘ＋ｙ：約５０ｘ／（ｘ＋ｙ）＝０.５各パクリタキセル２０ｍｇおよび各ＰＥＧ−ＰＢＬＡ１
２−５０Ｐ.Ｈ.５０％１００ｍｇを、それぞれスクリュ
ー管瓶に秤量し、アセトン２.０ｍＬを加え、攪拌溶解
する。次に窒素ガスを吹き付けることによりほとんどの
アセトンを除去し更に減圧下で乾燥することによりアセ
トンを完全に除去する。これらにそれぞれ水１０ｍＬを
加え密栓し、４℃（実施例１）、１０℃（実施例２）、
２０℃（実施例３）、２５℃（実施例４）、３０℃（実
施例５）、４０℃（比較例１）および６０℃（比較例
２）で一昼夜激しく攪拌した後、超音波処理（１３０
Ｗ、１秒 パルス １０分間）をし、一部サンプルをとり
ダイナミック光散乱光度計（大塚電子（株）、ＤＬＳ−
７０００ＤＨ型）を使用し粒子径の測定を行った。さら
にマクロゴール４０００を２０ｍｇ／ｍＬおよびマルト
ースを４０ｍｇ／ｍＬ濃度になるように添加溶解し、ド
ライアイスアセトン寒剤で凍結し、凍結乾燥製剤を調製
した。N: number such that the molecular weight of poly (ethylene glycol) is about 12000 x + y: about 50 x / (x + y) = 0.5 20 mg of each paclitaxel and each PEG-PBLA1
100 mg of 2-50 pH 50% is weighed in each screw tube bottle, 2.0 mL of acetone is added, and dissolved by stirring. Next, most of the acetone is removed by blowing nitrogen gas, and the acetone is completely removed by drying under reduced pressure. To each of these, 10 mL of water was added, and the bottles were tightly closed, and then 4 ° C (Example 1), 10 ° C (Example 2)
After vigorous stirring at 20 ° C. (Example 3), 25 ° C. (Example 4), 30 ° C. (Example 5), 40 ° C. (Comparative Example 1) and 60 ° C. (Comparative Example 2) for one day, ultrasonic treatment ( 130
W, 1 second pulse 10 minutes), take a part of the sample, and use dynamic light scattering photometer (Otsuka Electronics Co., Ltd., DLS-).
7,000 DH type) was used to measure the particle size. Further, Macrogol 4000 was added and dissolved to a concentration of 20 mg / mL and maltose at a concentration of 40 mg / mL, and frozen with a dry ice-acetone cryogen to prepare a freeze-dried preparation.
【００２９】超音波処理後の平均粒子径を以下表１に示
す。The average particle size after ultrasonic treatment is shown in Table 1 below.
【００３０】[0030]
【表１】[Table 1]
【００３１】なお、表１の結果を、攪拌温度を横軸に、
平均粒径が２２０ｎｍ以下の薬物封入ポリマーミセルの
割合を縦軸にプロットした結果を図１に示す。それぞれ
の回帰直線は（ｙ＝９８.８８８−０.７８１３５ｘ
Ｒ＝０.９８４７４ ｙ＝１４０.４９−２.１４２１
ｘ Ｒ＝０.９９３９７）であった。The results of Table 1 are shown in FIG.
The results of plotting the ratio of drug-encapsulating polymer micelles having an average particle size of 220 nm or less on the vertical axis are shown in FIG. Each regression line is (y = 98.888-0.78135x
R = 0.98474 y = 140.49-2.4211
x R = 0.99397).
【図１】実施例１〜５および比較例１、２による２２０
ｎｍ以下の粒子が占める割合の変化を示すグラフであ
る。FIG. 1 illustrates 220 according to Examples 1 to 5 and Comparative Examples 1 and 2.
It is a graph which shows change of the ratio which the particle below nm occupies.
─────────────────────────────────────────────────────フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考） Ａ６１Ｋ 31/519 Ａ６１Ｋ 31/519 31/704 31/704 31/7048 31/7048 33/24 33/24 47/34 47/34 Ａ６１Ｐ 35/00 Ａ６１Ｐ 35/00 Ｆターム(参考） 4C076 AA22 AA29 BB01 CC27 EE23B EE26B FF15 FF16 4C086 AA01 BA02 CB01 CB09 CB19 EA10 HA12 MA02 MA05 MA23 MA44 MA52 NA11 ZB26─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl.7 Identification code FI theme code (reference) A61K 31/519 A61K 31/519 31/704 31/704 31/7048 31/7048 33/24 33/24 47 / 34 47/34 A61P 35/00 A61P 35/00 F term (reference) 4C076 AA22 AA29 BB01 CC27 EE23B EE26B FF15 FF16 4C086 AA01 BA02 CB01 CB09 CB19 EA10 HA12 MA02 MA05 MA23 MA44 MA52 NA11 ZB26
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002150890AJP2003342168A (en) | 2002-05-24 | 2002-05-24 | Method for producing polymer micelle preparation containing drug for injection |
| AU2003235381AAU2003235381A1 (en) | 2002-05-24 | 2003-05-21 | Method for preparing polymer micelle pharmaceutical preparation containing drug for injection |
| KR10-2004-7017323AKR20050009992A (en) | 2002-05-24 | 2003-05-21 | Method for preparing polymer micelle pharmaceutical preparation containing drug for injection |
| PCT/JP2003/006334WO2003099260A1 (en) | 2002-05-24 | 2003-05-21 | Method for preparing polymer micelle pharmaceutical preparation containing drug for injection |
| EP03755278AEP1508331A1 (en) | 2002-05-24 | 2003-05-21 | Method for preparing polymer micelle pharmaceutical preparation containing drug for injection |
| CA002487117ACA2487117A1 (en) | 2002-05-24 | 2003-05-21 | Method for preparing polymer micelle pharmaceutical preparation containing drug for injection |
| US10/515,388US20060057219A1 (en) | 2002-05-24 | 2003-05-21 | Method for preparing a polymer micelle pharmaceutical preparation containing drug for injection |
| CNB038118807ACN100352426C (en) | 2002-05-24 | 2003-05-21 | Method for preparing polymer micelle pharmaceutical preparation containing drug for injection |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002150890AJP2003342168A (en) | 2002-05-24 | 2002-05-24 | Method for producing polymer micelle preparation containing drug for injection |
| Publication Number | Publication Date |
|---|---|
| JP2003342168Atrue JP2003342168A (en) | 2003-12-03 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2002150890APendingJP2003342168A (en) | 2002-05-24 | 2002-05-24 | Method for producing polymer micelle preparation containing drug for injection |
| Country | Link |
|---|---|
| US (1) | US20060057219A1 (en) |
| EP (1) | EP1508331A1 (en) |
| JP (1) | JP2003342168A (en) |
| KR (1) | KR20050009992A (en) |
| CN (1) | CN100352426C (en) |
| AU (1) | AU2003235381A1 (en) |
| CA (1) | CA2487117A1 (en) |
| WO (1) | WO2003099260A1 (en) |
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